Photodynamic therapy is an experimental form of treatment for cancer. It involves the localized or systemic administration of a photosensitizing compound or a metabolic precursor thereof, followed by exposure of the malignant tissue and adjacent normal tissues to photoactivating light. The tissue specificity of the resultant phototoxic damage is determined largely (though not entirely) by the relative concentrations of the photosensitizer in each tissue at the time of its exposure to the photoactivating light. Following systemic administration, certain derivatives of porphyrins, phthalocyanines, and chlorins accumulate preferentially within malignant tissues. At present a proprietary preparation of hematoporphyrin derivatives known under the tradename "Photofrin.RTM. II" is undergoing clinical evaluation for the treatment of carcinomas involving the bladder, esophagus, lung, brain, and other anatomical sites. In addition, 5-aminolevulinic acid, a precursor of protoporphyrin IX in the biosynthetic pathway for heme, is now being used to selectively induce photosensitizing concentrations of protoporphyrin IX in basal cell carcinomas and squamous cell carcinomas as described in U.S. patent application Ser. No. 386,414 which is assigned to the present assignee. In suitable clinical circumstances, both "Photofrin.RTM. II" and protoporphyrin IX induced by 5-aminolevulinic acid show a clinically useful degree of specificity for malignant tissues. However, not all porphyrins, phthalocyanines, or chlorins accumulate preferentially in tumors.
Injections of hematoporphyrin derivatives such as, but not limited to, Photofrin.RTM. II cause a clinically significant degree of skin photosensitization that persists for at least two weeks and sometimes for as long as four months. During this photosensitive period the patient must avoid exposure to sunlight, even sunlight that has been filtered through window glass. Clearly this deleterious side effect causes considerable inconvenience to patients and severely limits the clinical usefulness of photodynamic therapy.
It is known that as malignant tumors enlarge from a single cell to a palpable nodule, their growth pattern is such that certain areas of tumor develop an inadequate blood supply. The cells in such zones are both poorly nourished and hypoxic. Some of these cells die, but others merely reduce their metabolic activity to a basal level. Such cells are relatively resistant to destruction by X-rays and gamma-rays, since (i) molecular oxygen is required for some of the radiation chemistry that can cause DNA damage and cell death, and (ii) quiescent cells are relatively resistant to radiation damage. Hypoxic and poorly nourished cells tend to be resistant to many types of chemotherapeutic agents also. Chemotherapeutic agents usually enter tissues via the blood, and malignant cells whose blood supply is inadequate may not receive a lethal dose. In addition the toxicity of many common chemotherapeutic agents is restricted primarily to cells that are in cell cycle. Consequently, malignant cells that are poorly nourished and/or hypoxic may survive courses of radiotherapy and/or chemotherapy that otherwise might have been curative. Such surviving cells may proliferate subsequently to cause a recurrence of the cancer.
Thus, a drug which shows sufficient preferential toxicity for hypoxic cells may be given in doses that should kill the hypoxic cells in tumors without causing unacceptable toxicity to the normally-oxygenated cells of non-malignant tissues. Such a drug might not be curative if given as the sole therapy, since only some of the cells in tumors are hypoxic but it would be a very useful adjunct to radiotherapy and/or chemotherapy, since these tend to kill well oxygenated cells preferentially. For example, certain nitro-containing compounds accumulate preferentially in hypoxic tissues where they cause preferential toxicity for the hypoxic cells.
Like most drugs, photochemotherapeutic agents usually enter malignant tissues by diffusion from capillaries. As a result, zones of tissue that are poorly supplied with capillaries will be exposed to relatively low concentrations of the compound, perhaps too low to be therapeutically effective, unless the compound has a special affinity for hypoxic or necrotic tissue. The primary mechanism by which most photosensitizers kill cells require effective contact between a molecule of photosensitizers and a molecule of oxygen. The probability that enough such contacts will take place within hypoxic tissue will be reduced if the concentration of the photosensitizer is low, but will increase if the concentration of the photosensitizer in the hypoxic tissue is increased. Attempting to do so simply by increasing the dose of photosensitizer that is administered may produce too high a concentration in vital non-malignant tissues. However, if the photosensitizer had a significant degree of affinity or specificity for hypoxic tissues, it would accumulate preferentially in such tissues.
Thus, there is a need for better photochemotherapeutic agents that are cleared rapidly from normal tissues and especially skin, and ones that are effective in the hypoxic areas of tumors.